Epstein-Barr Virus (EBV) is an ubiquitous human herpes virus associated with Burkitt's lymphoma and nasopharyngeal carcinoma. EBV has also been associated with the development of lymphoproliferative syndromes in immunocompromised patients. EBV has recently been found to encode a gene (BCRF1) that is highly homologous to the human interleukin IL-10. IL-10 inhibits the production of interferon-gamma and tumor necrosis-alpha by natural killer (NK) and T lymphocytes. These cytokines inhibit the in vitro activation and transformation of human B lymphocytes by EBV and may play a role in controlling initial EBV infection and persistence. BCRF1 protein secretion by EBV-infected cells could thus serve to counteract cytokine-mediated immune responses to EBV infection. This proposal describes a method of producing strains of EBV that are mutant at the BCRF1 locus. These mutant viruses will be used to examine the extent to which the BCRF1 protein modulates the inhibitory effects of NK and T cells on various aspects of EBV infection. Specifically, it will be determined whether the mutant viruses are impaired in their ability to induce cell proliferation, immunoglobulin secretion, and transformation of infected B cells. Isolation of the BCRF1 protein from various.. EBV-infected cells and clinical samples will be attempted to characterize its pattern of expression. Finally, the potential role of the BCRF1 protein in lymphoproliferative syndromes will be studied by the development of the SCID mouse model. This model will be used for a comparative study of the tumorigenicity and in vivo behavior of BCRFl-negative and wild-type EBV.